Crystalline sodium atorvastatin

ABSTRACT

Crystalline sodium atorvastatin, compositions containing the same and methods for the production thereof.

The present invention relates to crystalline sodium atorvastatin, tocompositions containing the same and to methods for the formationthereof.

Cerebrovascular disease is often considered to be one of the biggestthreats to human health. According to one investigation, there are morethan three million people who die of the disease annually in China, thedisease being responsible for 50% of all deaths. 75% of survivors losetheir working abilities in different degrees and 4% are badly affected.Moreover, 80% of adults aged thirty or above may have cerebrovasculardisease in one of its forms, such as hyperlipemia, hypertension,coronary heart disease (CHD), and cerebral apoplexy.

Atherosclerosis is the pathological basis of ischemic cerebrovasculardisease (ICVD). Death rates due to central brain related coronary heartdisease and cerebrovascular disease have recently increased and,therefore, research into treatments for atherosclerosis is becoming moreand more important.

Atherosclerosis is the aggradation of blood ingredients, hyperplasia ofsmooth muscle cells and of collagenous fibre in the artery endothelium.The lesions, which result from an excessive,inflammatory-fibroproliferative response to various forms of injury tothe endothelium and smooth muscle of the artery wall, affect largeelastic arteries, such as the main artery and its first branch, andmedium muscle arteries, such as cerebral arteries, coronary arteries,renal arteries and arterial branches of arteries at the extremities.Lesions are commonly found at the openings of vas endothelium brancheswhich are easily damaged. The lesions are plaque-distributed and forcethe vas to be harder, narrow or block the chamber and then result inabsence of blood in the tissues and organs. Hence, the most likelyeffect is myocardial infarction and cerebral infarction. The cause ofatherosclerosis is not fully understood because of the many complexfactors involved in this disease. In general, there are two main typesof factors, the first being constitutional factors such as age, sex andfamilial inheriting factors, and the second being acquired factors, suchas hyperlipemia, hypertension, over-smoking, diabetes andover-adiposity. All of these will affect and increase theatherosclerosis owing to their collective multifactorial actions.

There are several kinds of anti-atherosclerosis drugs, such as lipidregulating agents, anti-oxidants, diluents of fatty acids and protectorsof arterial endothelium. The HMG-CoA Reductase Inhibitors are lipidregulating agents and include drugs of the statin family, such asmevastatin, lovastatin, simvastatin, fluvastatin and atorvastatin, whichare considered to be the best cholesterol lowering statin medicinesavailable. All are the first choice for treating diseases such asprimary hyperlipemia, heterozygote familial hiperlipemia, highlipoprotein (III), diabetes and renal hyperlipemia. There are a largenumber of scientists researching these kinds of medicines and they havealready reported a number of technical methods. For example, the abilityto obtain a high purity of HMG-CoA Reductase Inhibitor, as disclosed inChinese patent application 9981076.0, relies on “displacement of colorspectrum” to separate the HMG-CoA Reductase Inhibitor.

Although this method results in a high purity of HMG-CoA ReductaseInhibitor with a high yield, a low cost and minimal effect on theecological balance, it applies the “displacement of color spectrum”technique at the same time as utilising a chromatographic column. Theprinciple is traditional laminar analysis, which always takes a longtime to perform and requires the skills of a professional researcher tooperate it. In addition, it is difficult to perform in large-scaleautomated production.

Accordingly, this method is used to purify small quantities of HMG-CoAReductase Inhibitor at a laboratory scale only. It is not used forpurifying atorvastatin because of the difficulty in regenerating thechromatographic column. Atorvastatin, which is a new generation of thestatin family antihyperlipemias, is used, among other things, for commonhyperlipemia or mixed hyperlipidemia, which result mainly from increasedblood cholesterol. It is especially useful for patients who areunresponsive to other medicines.

It is thought that some of the statin family medicines have goodefficacy when they are used with other antihyperlipemia drugs, however,atorvastatin has been shown to have sufficient efficacy whenadministered alone. Hence, the sales of atorvastatin are increasingdramatically such that it is now the best selling statin family medicineon the market.

Chinese patent application number 02815070.8 discloses methods for theproduction of crystalline calcium atorvastatin. It discloses twocrystalline forms, VI and VII of [R—(R<*>,R<*>)]-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt. According to the methods, nine steps are needed toisolate Form VI and five steps to isolate Form VII. The crystallinecalcium atorvastatin produced is more than 99.0% pure by HPLC, however,due to the complex purifying process, the methods used are veryexpensive. The methods also require the use of nitrile as a purifyingagent which is not only harmful to the environment, but also to theworkers involved.

It is, therefore, an object of the present invention to seek toalleviate these problems.

A further object of the present invention is to provide crystallinesodium atorvastatin in various polymorphic forms and processes for thepreparation thereof.

According to a first aspect of the present invention, there is providedcrystalline sodium atorvastatin.

According to another aspect of the present invention, there is providedcrystalline sodium atorvastatin which exhibits an X-ray diffractionpattern comprising peaks expressed in degrees two-theta at approximately6.85±0.2, 7.18±0.2, 8.33±0.2, 19.1±0.2 and 19.42±0.2.

According to another aspect of the present invention, there is providedcrystalline sodium atorvastatin which exhibits an X-ray diffractionpattern comprising peaks expressed in degrees two-theta at approximately3.67±0.2, 5.05±0.2, 6.85±0.2, 7.18±0.2, 8.33±0.2, 8.62±0.2, 9.38±0.2,10.02±0.2, 10.35±0.2, 10.71±0.2, 11.76±0.2, 12.66±0.2, 13.87±0.2,16.01±0.2, 16.38±0.2, 17.1±0.2, 19.1±0.2, 19.42±0.2, 20.88±0.2,21.16±0.2, 22.9±0.2, 23.6±0.2, 30.12±0.2, 33.12±37.92±0.2 and 41.47350.2.

Also provided by the present invention is crystalline sodiumatorvastatin which exhibits an X-ray diffraction pattern substantiallythe same as shown in FIG. 2.

According to further aspect of the present invention, there is provideda method for the preparation of crystalline sodium atorvastatin, themethod comprising:

-   -   (a) adding amorphous sodium atorvastatin to a first organic        solvent to form a first solution;    -   (b) adding a second organic solvent to the first solution to        form a second solution;    -   (c) allowing sodium atorvastatin to crystallize out from the        solution; and    -   (d) collecting the crystallized sodium atorvastatin.

Preferably, the first organic solvent is an alcohol, more preferably astraight or branched C₁ to C₆ alcohol, further preferably ethanol.

In preferred embodiments, the second organic solvent is a ketone, morepreferably butanone.

Preferably, the amorphous sodium atorvastatin is added to the firstorganic solvent at a ratio of about 8 to 10 g amorphous atorvastatin forabout every 40 g to 100 g first organic solvent.

Preferably, the second organic solvent is added to the first solution ata ratio of about 50 to 100 g second organic solvent for about every 8 to10 g amorphous atorvastatin used in step (a).

The first organic solvent preferably comprises at least about 75%organic solvent in solution. Preferably, the crystallized sodiumatorvastatin is collected by filtration. It is preferred that thecollected crystallized sodium atorvastatin is dried, more preferablydried under vacuum.

In further embodiments of the present invention, the method comprisesthe following additional steps for the preparation of amorphous sodiumatorvastatin for use in step (a):

-   -   (i) preparing a third solution comprising sodium atorvastatin;    -   (ii) adjusting the pH of the third solution to an acid pH;    -   (iii) adding a third organic solvent to form a fourth solution;    -   (iv) isolating an organic layer;    -   (v) adjusting the pH of the organic layer to an alkali pH;    -   (vi) collecting precipitated amorphous sodium atorvastatin.

Preferably, the third solution comprises about 5% sodium atorvastatin.

Preferably, the pH of the third solution is adjusted by the addition ofhydrochloric acid, preferably having a concentration of about 15 to 30%,more preferably about 15 to 20%. In preferred embodiments, the pH of thethird solution is adjusted to between about 1 and 4.

Preferably, the third organic solvent is a halogen substituted C₁ to C₆hydrocarbon, more preferably dichloromethane.

It is preferred that the third organic solvent is added to the thirdsolution at a ratio of about 100 to 200 g third organic solvent forabout every 10 g sodium atorvastatin in the third solution.

Preferably, the pH of the organic layer is adjusted by the addition ofsodium hydroxide solution, preferably having a concentration of about 20to 50%. In preferred embodiments, the pH of the organic layer isadjusted to between about 9 and 10.

Preferably, the precipitated amorphous sodium atorvastatin is collectedby filtration.

Preferably, the precipitated amorphous sodium atorvastatin is dried,more preferably dried under vacuum.

According to a preferred embodiment, the precipitated amorphous sodiumatorvastatin exhibits an X-ray diffraction pattern substantially thesame as shown in FIG. 1.

According to another embodiment the precipitated amorphous sodiumatorvastatin preferably exhibits an X-ray diffraction pattern comprisingpeaks expressed in degrees two-theta at approximately 7.87±0.2,18.18±0.2, 18.87±0.2 and 22.88±0.2.

According to a further embodiment, the precipitated amorphous sodiumatorvastatin preferably exhibits an X-ray diffraction pattern comprisingpeaks expressed in degrees two-theta at approximately 5.45±0.2,7.87±0.2, 9.52±0.2, 11.02±0.2, 14.2±0.2, 16.4±0.2, 18.18±0.2, 18.87±0.2,19.76±0.2, 22.88±0.2, 32.27±0.2, 33.35±0.2, 37.86±0.2, 39.99±0.2,41.13±0.2 and 44.95±0.2.

A further aspect of the present invention relates to amorphous sodiumatorvastatin.

According to another aspect of the present invention, there is providedamorphous sodium atorvastatin which exhibits an X-ray diffractionpattern comprising peaks expressed in degrees two-theta at approximately7.87±0.2, 18.18±0.2, 18.87±0.2 and 22.88±0.2.

According to a further aspect of the present invention, there isprovided amorphous sodium atorvastatin which exhibits an X-raydiffraction pattern comprising peaks expressed in degrees two-theta atapproximately 5.45±0.2, 7.87±0.2, 9.52±0.2, 11.02±0.2, 14.2±0.2,16.4±0.2, 18.18±0.2, 18.87±0.2, 19.76±0.2, 22.88±0.2, 32.27±0.2,33.35±0.2, 37.86±0.2, 39.99±0.2, 41.13±0.2 and 44.95±0.2.

Also provided by the present invention is amorphous sodium atorvastatinwhich exhibits an X-ray diffraction pattern substantially the same asshown in FIG. 1.

Further provided by the present invention is amorphous sodiumatorvastatin produced by any of the methods described herein.

The present invention also relates to crystalline sodium atorvastatinproduced by any of the methods described herein.

Preferably, the crystalline sodium atorvastatin has a purity of at least95%, more preferably at least 98%, further preferably at least 99%.

Preferably, the amorphous sodium atorvastatin has a purity of at least90%, more preferably at least 93%, further preferably at least 96%,preferably still at least 98%.

Accordingly, the present invention describes a novel crystalline form ofsodium atorvastatin, a novel amorphous form of sodium atorvastatin andprocesses for the preparation thereof.

It is anticipated that both the crystalline form of sodium atorvastatinand the amorphous form of sodium atorvastatin disclosed herein will beuseful in the treatment of a variety of diseases which are prevented,ameliorated or eliminated by the administration of a lipid regulatingagent. Examples of such diseases include hyperlipemia, primaryhyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia,mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronaryheart disease, cerebral apoplexy and ischemic cerebrovascular disease.

According to another aspect of the present invention, there is,therefore, provided a pharmaceutical composition comprising crystallinesodium atorvastatin or amorphous sodium atorvastatin as describedherein.

According to a further aspect of the present invention, there isprovided a composition for treating a disease which is prevented,ameliorated or eliminated by the administration of a lipid regulatingagent, the composition comprising crystalline sodium atorvastatin oramorphous sodium atorvastatin as described herein.

Preferably, the disease is selected from hyperlipemia, primaryhyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia,mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronaryheart disease, cerebral apoplexy and ischemic cerebrovascular disease.

Also provided by the present invention is a method of treating a diseasewhich is prevented, ameliorated or eliminated by the administration of alipid regulating agent, the method comprising administering to a patienta therapeutically effective amount of crystalline sodium atorvastatin,amorphous sodium atorvastatin, or a pharmaceutical composition asdescribed herein.

Preferably, the disease is selected from hyperlipemia, primaryhyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia,mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronaryheart disease, cerebral apoplexy and ischemic cerebrovascular disease.

By a therapeutically effective amount, it is meant an amount which iscapable of preventing, ameliorating or eliminating the diseasesmentioned herein.

The crystalline sodium atorvastatin or amorphous sodium atorvastatin canbe mixed with a carrier, diluent or excipient therefor, all of which arewell known in the art. For example, suitable carriers may include pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols, ointments, soft and hard gelatine capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

According to a further aspect of the present invention, there isprovided a process for preparing the crystalline form of sodiumatorvastatin with high purity, the method comprising the followingsteps:

-   -   (a) preparation of amorphous sodium atorvastatin: starting with        a sodium atorvastatin solution, adjust the pH to about 1-4 with        acid solution, extract with organic solvent, adjust the pH in        the organic layer to about 9-10, and collect the precipitate by        filtration. Obtain the amorphous sodium atorvastatin after        drying under vacuum.    -   (b) preparation of crystalline sodium atorvastatin: dissolve the        obtained amorphous sodium atorvastatin in aqueous alcoholic        solvent, add butanone, allow the sodium atorvastatin to        crystallize out at low temperature. Collect the crystalline        material by filtration and then dry under vacuum.

Preferably, the acid solution used is hydrochloric acid with aconcentration ranging from about 15% to 30%. Preferably, the basicsolution used is sodium hydroxide solution with a concentration rangingfrom about 20% to 50%. In preferred embodiments, the organic solventused is dichloromethane, which is in a mass ratio of about 10-20:1against the amount of sodium atorvastatin in the solution. The aqueousalcoholic solvent used is preferably ethanol, the amount of ethanol usedis preferably in a mass ratio of about 4-10:1 against the amount ofsodium atorvastatin in solution. The ketone solvent used is preferablybutanone, the amount of butanone used is preferably in a mass ratio ofabout 5-10:1 against the amount of sodium atorvastatin in solution.

The present invention thus provides a crystalline form of sodiumatorvastatin with a high purity. The common practice to prepare calciumatorvastatin usually involves the replacement of sodium with calcium insolution in which the sodium atorvastatin serves only as intermediatewithout isolation. Therefore, the quality of the isolated calcium saltis not satisfactory in terms of purity. The present invention provides acrystallization process for preparing crystalline sodium atorvastatinwith high purity, which can be either used as a pharmaceuticalingredient or converted to calcium atorvastatin with high purity.

An example of the present invention will now be described with referenceto the accompanying figures in which:

FIG. 1 is the powder X-ray diffraction pattern for amorphous sodiumatorvastatin; and

FIG. 2 is the powder X-ray diffraction pattern for the crystallinesodium atorvastatin of the present invention.

CRYSTALLISATION Example 1

A solution (200 g) containing 10 g of sodium atorvastatin was added to a500 ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200 g)was added, and then the pH of the organic layer was adjusted to 10 witha 50% sodium hydroxide solution. The precipitate was collected byfiltration and then dried under vacuum. Amorphous sodium atorvastatin,designated as Form I, (8.2 g) was thus obtained having an X-ray powderdiffraction pattern was shown in FIG. 1.

The amorphous sodium atorvastatin (8.2 g) was dissolved in an 88%ethanol solution (50 g). Butanone (60 g) was then added. The sodiumatorvastatin crystallized out on cooling. The crystalline sodiumatorvastatin was collected by filtration and dried under vacuum (7.5 g).Highly pure crystalline sodium atorvastatin, designated as Form II, wasobtained with an assay purity of 99.4% and a crystal form having an XRDspectrum shown in FIG. 2.

Example 2

A solution (200 g) containing 10 g of sodium atorvastatin was added to a500 ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200 g)was added, and then the pH of the organic layer was adjusted to 10 witha 50% sodium hydroxide solution. The precipitate was collected byfiltration and then dried under vacuum. Amorphous sodium atorvastatin,designated as Form I, (8.2 g) was thus obtained having an X-ray powderdiffraction pattern was shown in FIG. 1.

The amorphous sodium atorvastatin (8.2 g) was dissolved in a 90% ethanolsolution (70 g). Butanone (80 g) was then added. The sodium atorvastatincrystallized out on cooling. The crystalline sodium atorvastatin wascollected by filtration and dried under vacuum (7.5 g). Highly purecrystalline sodium atorvastatin, designated as Form II, was obtainedwith an assay purity of 99.5% and a crystal form having an XRD spectrumshown in FIG. 2.

Example 3

Hydrochloric acid having a concentration of 15-20% was added to asolution containing sodium atorvastatin and the pH was adjusted to 1-4.Dichloromethane was added to the solution and the organic layer wasmixed with 20-50% sodium hydroxide solution until the pH was at 9-10.Generally, the amount of sodium hydroxide used was at a ratio of 10-20times the amount of sodium atorvastatin used. The precipitate was thencollected by filtration and dried under vacuum. Amorphous sodiumatorvastatin, designated as Form I, was thus obtained having an XRDspectrum as shown in FIG. 1.

The amorphous sodium atorvastatin was dissolved in an ethanol solutionat a ratio of about 4-10 times the amount of sodium atorvastatin used.Butanone was added to the solution at a ration of about 5-10 times theamount of sodium atorvastatin used. Sodium atorvastatin was allowed tocrystallize out at a lower temperature, collected by filtration and thendried under vacuum. Highly pure crystalline sodium atorvastatin,designated as Form II, was obtained having an XRD spectrum shown in FIG.2.

Example 4

A solution (200 g) containing 10 g of sodium atorvastatin was added to a500 ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200 g)was added, and then the pH of the organic layer was adjusted to 10 witha 50% sodium hydroxide solution. The precipitate was collected byfiltration and then dried under vacuum. Amorphous sodium atorvastatin,designated as Form I, (8.2 g) was thus obtained having an X-ray powderdiffraction pattern was shown in FIG. 1.

The amorphous sodium atorvastatin (8.2 g) was dissolved in a 85% ethanolsolution (50 g). Butanone (60 g) was then added. The sodium atorvastatincrystallized out on cooling. The crystalline sodium atorvastatin wascollected by filtration and dried under vacuum (7.5 g). Highly purecrystalline sodium atorvastatin, designated as Form II, was obtainedwith an assay purity of 99.4% and a crystal form having an XRD spectrumshown in FIG. 2.

Example 5

A solution (200 g) containing 10 g of sodium atorvastatin was added to a500 ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200 g)was added, and then the pH of the organic layer was adjusted to 10 witha 50% sodium hydroxide solution. The precipitate was collected byfiltration and then dried under vacuum. Amorphous sodium atorvastatin,designated as Form I, (8.2 g) was thus obtained having an X-ray powderdiffraction pattern was shown in FIG. 1.

The amorphous sodium atorvastatin (8.2 g) was dissolved in a 90% ethanolsolution (70 g). Butanone (60 g) was then added. The sodium atorvastatincrystallized out on cooling. The crystalline sodium atorvastatin wascollected by filtration and dried under vacuum (7.3 g). Highly purecrystalline sodium atorvastatin, designated as Form II, was obtainedwith an assay purity of 99.5% and a crystal form having an XRD spectrumshown in FIG. 2.

The sodium atorvastatin salt produced by the above methods had thefollowing structure:

TABLE 1

The XRD spectrum for the amorphous form obtained according to theexamples above. 2theta (degree) d (A) I/I₀ I.cps FWHM 5.451 16.1985 10.3291 7.865 11.2313 74.7 2107 9.516 9.2868 5.1 145 11.018 8.0237 9.5 26914.201 6.2317 14.6 413 16.399 5.4009 29.4 829 0.20 18.179 4.8758 1002820 18.873 4.6982 67.2 1894 19.761 4.4890 29.1 821 22.875 3.8844 87.52468 0.36 32.271 2.7717 12.9 363 33.354 2.6842 7.0 197 37.860 2.374416.4 462 39.994 2.2525 6.2 176 41.129 2.1929 5.0 140 44.947 2.0151 6.3179 Peak Number: 16 Highest Peak: 2820 Total Diffraction Intensity:3453641 Total Purity Intensity: 798951 Total Purity Intensity/TotalDiffraction Intensity: 0.231

TABLE 2 The XRD spectrum for the crystalline form obtained according tothe examples above. 2theta (degree) d (A) I/I₀ I.cps FWHM 3.667 24.076957.2 1349 0.36 5.045 17.5033 26.2 617 0.31 6.850 12.8933 70.2 1656 0.347.180 12.3016 76.5 1804 0.53 8.331 10.6046 93.8 2213 0.31 8.615 10.255652.4 1237 0.20 9.375 9.4252 29.2 688 0.31 10.022 8.8190 32.7 772 0.2210.347 8.5426 36.9 871 0.25 10.712 8.2518 15.5 365 0.22 11.760 7.518917.8 420 0.34 12.658 6.9874 11.1 261 0.22 13.872 6.3784 11.4 269 0.2216.006 5.5325 36.5 860 0.34 16.376 5.4086 47.2 1113 0.42 17.104 5.179950.3 1186 0.56 19.100 4.6428 100 2359 0.50 19.423 4.5663 78.5 1853 0.4820.879 4.2511 21.1 497 0.22 21.155 4.1963 20.5 484 0.20 22.901 3.880123.4 551 0.25 23.602 3.7664 27.4 647 0.22 30.121 2.9645 10.2 240 0.2033.120 2.7025 8.5 200 0.20 37.923 2.3706 15.1 356 41.471 2.1756 7.7 182Peak Number: 26 Highest Peak: 2359 Total Diffraction Intensity: 3380617Total Purity Intensity: 711366 Total Purity Intensity/Total DiffractionIntensity: 0.21

1. A method for the preparation of crystalline sodium atorvastatin, themethod comprising: (a) adding amorphous sodium atorvastatin to a firstorganic solvent to form a first solution; (b) adding a second organicsolvent to the first solution to form a second solution; (c) allowingsodium atorvastatin to crystallize out from the solution; and (d)collecting the crystallized sodium atorvastatin, wherein the firstorganic solvent is ethanol and wherein the second organic solvent isbutanone thereby obtaining crystalline sodium atorvastatin whichexhibits an X-ray diffraction pattern comprising peaks expressed indegrees two-theta at approximately 3.67±0.2, 5.05±0.2, 6.85±0.2,7.18±0.2, 8.33±0.2, 8.62±0.2, 9.38±0.2, 10.02±0.2, 10.35±0.2, 10.71±0.2,11.76±0.2, 12.66±0.2, 13.87±0.2, 16.01±0.2, 16.38±0.2, 17.1±0.2,19.1±0.2, 19.42±0.2, 20.88±0.2, 21.16±0.2, 22.9±0.2, 23.6±0.2,30.12±0.2, 33.12±0.2, 37.92±0.2 and 41.47±0.2.
 2. A method according toclaim 1, wherein the amorphous sodium atorvastatin is added to the firstorganic solvent at a ratio of about 8 to 10 g amorphous atorvastatin forabout every 40 g to 100 g first organic solvent.
 3. A method accordingto claim 1, wherein the second organic solvent is added to the firstsolution at a ratio of about 50 to 100 g second organic solvent forabout every 8 to 10 g amorphous atorvastatin used in (a).
 4. A methodaccording to claim 1, wherein the first organic solvent comprises atleast about 75% organic solvent in solution.
 5. A method according toclaim 1, wherein the crystallized sodium atorvastatin is collected byfiltration.
 6. A method according to claim 1, wherein the collectedcrystallized sodium atorvastatin is dried.
 7. A method according toclaim 6, wherein the collected crystallized sodium atorvastatin is driedunder vacuum.
 8. A method according to claim 1, comprising the followingfor the preparation of amorphous sodium atorvastatin for use in step(a): (i) preparing a third solution comprising sodium atorvastatin; (ii)adjusting the pH of the third solution to an acid pH; (iii) adding athird organic solvent to form a fourth solution; (iv) isolating anorganic layer; (v) adjusting the pH of the organic layer to an alkalipH; and (vi) collecting precipitated amorphous sodium atorvastatin,wherein the third organic solvent is dichloromethane.
 9. A methodaccording to claim 8, wherein the third solution comprises about 5%sodium atorvastatin.
 10. A method according to claim 8, wherein the pHof the third solution is adjusted by the addition of hydrochloric acid.11. A method according to claim 10, wherein the hydrochloric acid has aconcentration of about 15 to 20%.
 12. A method according to claim 8,wherein the pH of the third solution is adjusted to between about 1 and4.
 13. A method according to claim 8, wherein the third organic solventis added to the third solution at a ratio of about 100 to 200 g thirdorganic solvent for about every 10 g sodium atorvastatin in the thirdsolution.
 14. A method according to claim 8, wherein the pH of theorganic layer is adjusted by the addition of sodium hydroxide solution.15. A method according to claim 14, wherein the sodium hydroxidesolution has a concentration of about 20 to 50%.
 16. A method accordingto claim 8, wherein the pH of the organic layer is adjusted to betweenabout 9 and
 10. 17. A method according to claim 8, wherein theprecipitated amorphous sodium atorvastatin is collected by filtration.18. A method according to claim 8, wherein the precipitated amorphoussodium atorvastatin is dried.
 19. A method according to claim 18,wherein the precipitated amorphous sodium atorvastatin is dried undervacuum.
 20. A method according to claim 8, wherein the precipitatedamorphous sodium atorvastatin exhibits an X-ray diffraction patternsubstantially the same as shown in FIG.
 1. 21. A method according toclaim 8, wherein the precipitated amorphous sodium atorvastatin exhibitsan X-ray diffraction pattern comprising peaks expressed in degreestwo-theta at approximately 5.45±0.2, 7.87±0.2, 14.2±0.2, 16.4 ±0.2,18.18±0.2, 18.87±0.2, 19.76±0.2, 22.88±0.2, 32.27±0.2, and 37.86 ±0.2.22. A method according to claim 8, wherein the precipitated amorphoussodium atorvastatin exhibits an X-ray diffraction pattern comprisingpeaks expressed in degrees two-theta at approximately 5.45±0.2,7.87±0.2, 9.52±0.2, 11.02 ±0.2, 14.2±0.2, 16.4±0.2, 18.18±0.2,18.87±0.2, 19.76±0.2, 22.88±0.2, 32.27 ±0.2, 33.35±0.2, 37.86±0.2,39.99±0.2, 41.13±0.2 and 44.95±0.2.
 23. A method according to claim 1,wherein the collected crystalline sodium atorvastatin has a purity of atleast 98%.
 24. A method according to claim 23, wherein the collectedcrystalline sodium atorvastatin has a purity of at least 99%.